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Aflatoxin B1 and Epstein–Barr virus-induced CCL22 expression stimulates B cell infection

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posted on 2024-05-24, 14:06 authored by Mohamed Ali Maroui, Grace Akinyi Odongo, Lucia Mundo, Francesca Manara, Fabrice Mure, Floriane Fusil, Antonin Jay, Tarik Gheit, Thanos M. Michailidis, Domenico Ferrara, Lorenzo Leoncinid, Paul Murray, Evelyne Maneta, Théophile Ohlmanna, Marthe De Boevree, Sarah De Saegere, François-Loïc Cosseta, Stefano Lazzid, Rosita Accardi, Zdenko Herceg, Henri Gruffata, Rita Khoueiry

Epstein–Barr Virus (EBV) infects more than 90% of the adult population worldwide. EBV infection is associated with Burkitt lymphoma (BL) though alone is not sufficient to induce carcinogenesis implying the involvement of co-factors. BL is endemic in African regions faced with mycotoxins exposure. Exposure to mycotoxins and oncogenic viruses has been shown to increase cancer risks partly through the deregulation of the immune response. A recent transcriptome profiling of B cells exposed to aflatoxin B1 (AFB1) revealed an upregulation of the Chemokine ligand 22 (CCL22) expression although the underlying mechanisms were not investigated. Here, we tested whether mycotoxins and EBV exposure may together contribute to endemic BL (eBL) carcinogenesis via immunomodulatory mechanisms involving CCL22. Our results revealed that B cells exposure to AFB1 and EBV synergistically stimulated CCL22 secretion via the activation of Nuclear Factor-kappa B pathway. By expressing EBV latent genes in B cells, we revealed that elevated levels of CCL22 result not only from the expression of the latent membrane protein LMP1 as previously reported but also from the expression of other viral latent genes. Importantly, CCL22 overexpression resulting from AFB1-exposure in vitro increased EBV infection through the activation of phosphoinositide-3-kinase pathway. Moreover, inhibiting CCL22 in vitro and in humanized mice in vivo limited EBV infection and decreased viral genes expression, supporting the notion that CCL22 overexpression plays an important role in B cell infection. These findings unravel new mechanisms that may underpin eBL development and identify novel pathways that can be targeted in drug development.

Funding

Impact of multi-mycotoxin exposure in early life on B cell epigenetic profile & infection by oncogenic viruses: unraveling interaction with immune regulatory cytokine profiles & co-infections in young children

Research Foundation - Flanders

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To evaluate the impact of seasonal dietary aflatoxin exposure of pregnant women in rural Africa by identifying biomarkers of exposure, growth impairment, and disease risk.

Bill & Melinda Gates Foundation

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VIRGO: Studying a VIRal Gpcr in Oncogenesis

European Commission

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History

Publication

Proceedings of the National Academy of Sciences, 2024, 121, (16), e2314426121

Publisher

Proceedings of the National Academy of Sciences

Also affiliated with

  • Health Research Institute (HRI)
  • Bernal Institute

Sustainable development goals

  • (3) Good Health and Well-being

Department or School

  • School of Medicine

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